APM Resident Education Curriculum Thomas W Heinrich MD Associate Professor of Psychiatry amp Family Medicine Chief Psychiatric Consult Service at Froedtert Hospital Department of Psychiatry amp Behavioral Medicine ID: 918448
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Slide1
Neuroleptic Malignant Syndrome and Serotonin Syndrome
APM Resident Education Curriculum
Thomas W. Heinrich, M.D.
Associate Professor of Psychiatry & Family Medicine
Chief, Psychiatric Consult Service at
Froedtert
Hospital
Department of Psychiatry & Behavioral Medicine
Medical College of Wisconsin
Slide2Historical Background
Syndrome malin des neuroleptiques
R
apidly
progressive neurovegatative stateObserved during early clinical trials of haloperidol1960Neuroleptic Malignant SyndromeFirst appeared in English literature in 1967Belated recognition in the U.S.
2
Slide3Incidence
Typical antipsychotics
B
est
estimate 0.1-0.2% (Caroff and Mann, 1996)Wide variance in estimates 0.1-3.0%Atypical antipsychoticsIt remains unclear whether atypical antipsychotics are less likely to cause NMS compared to typical antipsychotics (Troller, et al., 2009)3
Slide4Pathogenesis
Central dopamine hypoactivity
Evidence
All antipsychotics implicated share dopamine receptor antagonismWithdrawal of dopamine agonists or “freezing” episodes in Parkinson’s disease have induced NMS-like statesDopamine agonists appear beneficial in treatmentDisruption of dopamine tracts produce NMS-like statesA case
report
utilizing SPECT revealed almost complete D2 receptor blockade in a patient with NMS
R
eduction
in CSF homovanillic acid (HVA) in NMS
Reduction persisted after recovery
4
Slide5Pathogenesis
Central dopamine hypoactivity
(continued)
Theory (Strawn et al, 2007, Fricchione 1985)Patients susceptible to developing NMS may have a baseline central hypodopaminergiaTrait vulnerabilityThe hypodopaminergic state is further stressed with pharmacologic or stress-induced reductions in dopamine activityState vulnerability
5
Slide6Clinical Characteristics
Early signs
C
hange
in mental statusExtrapyramidal symptoms unresponsive to antiparkinsonian agentsAutonomic dysfunction6
Slide7Clinical Characteristics
Signs
and Symptoms
H
yperthermia98%Muscle rigidity - “lead pipe rigidity”97%Mental status changes - delirium and catatonia97%7
Slide8Clinical Characteristics
Signs and symptoms
(continued)
A
utonomic dysfunctionTachycardia88%Profuse diaphoresisLabile blood pressure61%Tachycardia or labile blood pressure95%
8
Slide9Clinical Characteristics
Laboratory findings
R
habdomyolysis
LeukocytosisLow serum ironMetabolic acidosisElectroencephalogramNeuroimaging9
Slide10Clinical Characteristics
Is there an “atypical” presentation of NMS with atypical antipsychotics?
A majority of cases of NMS produced by atypical antipsychotics present with “typical” NMS signs and symptoms
However…
Clozapine, however, appears to present with a lower incidence of rigidity (at least early in the course of the syndrome) when compared to the other atypical antipsychoticsCase reports of aripiprazole-induced NMS suggest a lower proportion of patients presenting with delirium and elevated temperature 10
Slide11Diagnostic Criteria
Caroff’s Criteria for NMS
Treatment with neuroleptics
H
yperthermia (>38C)Muscle rigidityFive of the followingChange in mental statusTachycardiaL
abile
blood pressure
D
iaphoresis
T
remorIncontinence
CK elevation
Leukocytosis
M
etabolic
acidosis
Exclusion of other causes
11
Slide12Diagnostic Criteria
DSM - IV TR
Severe muscle rigidity and elevated temperature associated with the use of neuroleptics
Two or more of the following
DiaphoresisDysphagiaTremorIncontinenceChange in consciousnessM
utism
T
achycardia
L
abile
blood pressureLeukocytosis
M
uscle
injury
Not due to medical, substance or
mental condition
12
Slide13Diagnostic Criteria
Levenson’s Criteria
Major manifestations
F
everRigidityElevated creatinine phosphokinase (CK) levelMinor manifestationsTachycardiaAbnormal blood pressure
T
achypnea
A
ltered
consciousness
DiaphoresisL
eukocytosis
Presence of all three major, or two major and
four minor, manifestations
indicates a high
probability
of NMS.
13
Slide14Risk Factors
Not risk factors
A
ge
SexEnvironmental factorsRisk factorsHeredityNeuropsychiatric diagnosisNMS is not specific to any specific neuropsychiatric diagnosis, but……Catatonia
O
rganic
brain disorders
14
Slide15Risk Factors
Risk factors
(continued)
P
hysiological statesAgitation and dehydrationHypodopaminergic traitPharmacological variablesHistory of NMS30-33% of NMS patients when rechallenged17% of NMS patients report similar past episodes
15
Slide16Risk Factors
Pharmacologic variables
E
xposure
to drugs that block dopamine D2 receptorsHigh potencyHigh dosageRapid dose escalation (Shalev & Munitz 1988) Study of 56 NMS cases1 episode with decreased dose4 episodes with steady state dosing51
cases with dose escalation
Range
40-6000
chlorpromazine equivalents/day
Average
of 500-700mg chlorpromazine/day
16
Slide17Risk Factors
Pharmacologic variables
D
epot
neurolepticsLonger durationLittle evidence of increased mortalityConcomitant medications33% have more than one antipsychotic>50% on additional non-neuroleptic medicationsAnticholinergics impair temperature regulation
17
Slide18Differential Diagnosis
Most common disorders mistaken for NMS
I
nfections
CatatoniaAgitated delirium“Benign” extrapyramidal side effects (EPS)Serotonin SyndromeSystemic disordersEPS with feverHormonal disordersT
hyrotoxicosis
P
heochromocytoma
18
Slide19Differential Diagnosis
Systemic disorders
(continued)
H
eatstrokeExertional heat strokeClassical heat strokeDrugsMalignant hyperthermiaSerotonin syndromeDopaminergic withdrawalL
evodopa
withdrawal
F
reezing
episodes in Parkinson’s disease
19
Slide20Differential Diagnosis
Central Nervous System Disorders
I
nfections
Structural pathologySeizuresMalignant catatoniaUnchecked hyperactivity leading to exhaustion, stupor, hyperthermia, and deathReported prior to the advent of neurolepticsNMS may represent an iatrogenic form of malignant catatonia
20
Slide21Clinical Course
Onset
R
elated
to initiation of neuroleptic treatment16% within one day66% by one week96% within 30 daysDurationSelf limited once neuroleptics are stopped9.6 +/- 9.1 days average length23% recovered in two days63% recovered in one week97% recovered in one month
21
Slide22Outcomes
Mortality
M
ortality
is decreasing (Shalev et al. 1989)25% before 198412% after 1984Risks for increased mortalityOlder ageHigher temperaturesDepot neuroleptics (?)Pre-existing brain pathology
D
evelopment
of renal failure
22
Slide23Outcomes
Morbidity
R
enal
insufficiency/failure16-25%Respiratory failureCardiac morbidityCognitive sequelae (?)23
Slide24Treatment
Basics
E
arly
recognitionCessation of neurolepticsHydrationTemperature reductionIntensive monitoringSupportive care
24
Slide25Treatments
Specific treatments
B
enzodiazepines
NMS may represent an iatrogenic malignant catatoniaDantroleneTheory81% of patients benefited1-10mg/kg/day in divided dosesOptimal length of treatment not establishedMay cause hepatic and respiratory compromise
25
Slide26Treatments
Specific treatments
(continued)
Dopaminergic medications
TheoryAmantadine63% found benefit as monotherapy200-400 mg/dayBromocriptine94% found benefit as monotherapyShortened time to clinical response2,5mg tid - 15mg tidLevodopa
26
Slide27Treatments
Specific treatments
(continued)
ECT
May increase dopamine synthesis and releaseECT considered if…Unresponsive to pharmacologic treatmentCatatonia cannot be ruled outResidual catatonia developsPsychosis develops following NMS
Mean
time to response is 1.46 +/- 2.38 days
27
Slide28Rough Treatment Guidelines
Mild or early NMS
Supportive care and benzodiazepines
Moderate NMS (rigidity and temperatures 38-40)
Dopamine agonistSevere NMS (rigidity, hypermetabolism, temperatures >40)Dantrolene28Strawn JR, Keck PE Jr,
Caroff
SN. Am J Psychiatry. 2007 Jun;164(6):870-6.
Slide29Antipsychotic Rechallenge
Guidelines for rechallenge
R
educe
potential risk factorsTwo weeks from resolution of NMSGradual titration of low starting dosesLow potency or atypical antipsychoticsIdeally rechallenge should occur in a hospital
29
Slide30Serotonin Syndrome
Serotonin syndrome can be a serious complication of treatment with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), and other serotonergic medications.
It usually occurs when 2 or more serotonin-modifying agents are used in combination.
Cases have been reported after single agent therapy.
30
Slide31Serotonin Syndrome
History
The syndrome was first described in the 1950s (Mitchell, 1955).
The patient exhibited restlessness, excitation, tremors, and hyper-reflexia during simultaneous administration of iproniazid (and anti-TB drug and MAOI) and Meperidine
Sternbach (1991) conducted the first comprehensive clinical review of serotonin syndrome31
Slide32Serotonin Syndrome
Incidence
Unknown
The variable nature of its presentation makes it difficult to diagnose and has caused underreporting
32
Slide33Serotonin Syndrome
Pathophysiology
Enhanced central serotonergic activity
The excessive serotonergic activity may influence other parts of the CNS
DopamineNorepinephrineReceptorsHyperstimulation of the 5-HT1A receptors33
Slide34Serotonin Syndrome
Pathophysiology (continued)
Hyperstimulation of the 5-HT1A and/or 5-HT2A receptors
5-HT1A
This relationship has been demonstrated in animals by the use of 5-HT1A agonists and antagonists to produce and block the syndrome, respectively5-HT2Nonspecific 5-HT receptor antagonists used in the treatment of human serotonin syndrome) have significantly greater potency at the 5-HT2 receptor compared with the 5-HT1A receptor
34
Slide35Serotonin Syndrome
Clinical characteristics (Physical)
Clinical triad
Cognitive/behavioral alterations
Confusion DeliriumAgitationLethargy ComaAutonomic instability
Hyperthermia
Tachycardia
Diaphoresis
Dilated pupils
Neuromuscular abnormalities
Myoclonus
Hyperreflexia
Rigidity
35
Slide36Serotonin Syndrome
Clinical characteristics (Laboratory)
There are no specific tests available for the diagnosis of serotonin syndrome.
Blood levels of serotonin do not correlate with clinical findings.
Nonspecific laboratory findings may include…Elevated total white blood cell count, CPK levels, and transaminases,Decreased serum bicarbonate level Severe cases can evolve to include…Disseminated intravascular coagulation, rhabdomyolysis, and metabolic acidosisRenal failure and myoglobinuriaAdult respiratory distress syndrome
36
Slide37Serotonin Syndrome
Sternbach’s suggested diagnostic criteria for serotonin syndrome
A.
Coincident with the addition of or increase in a known serotonergic agent to an established medication regimen, at least three of the following clinical features are present:
1. Mental status changes (confusion, hypomania),2. Agitation,3. Myoclonus,4. Hyperreflexia,5. Diaphoresis,6. Shivering,7. Tremor,8. Diarrhea,
9. Lack of coordination,
10. Fever.
B.
Other etiologies (e.g. infectious, metabolic, substance abuse, or withdrawal) have been ruled out.
C.
A neuroleptic had not been started or increased in dosage prior to the onset of the signs and symptoms listed above.
Sternbach H. The serotonin syndrome.
Am J Psychiatry
1991;
148(6):
705-713.
37
Slide38Serotonin Syndrome
Revised diagnostic criteria for serotonin syndrome
Addition of a serotonergic agent to an already established treatment (or increase in dosage) and manifestation of at least 4 major symptoms or 3 major symptoms plus 2 minor ones
Mental (cognitive and behavioral) symptoms
Major symptoms: confusion, elevated mood, coma or semicomaMinor symptoms: agitation and nervousness, insomniaAutonomic symptomsMajor symptoms: fever, hyperhidrosisMinor symptoms: tachycardia, tachypnea and dyspnea, diarrhea, low or high blood pressure
Neurological symptoms
Major symptoms: myoclonus, tremors, chills, rigidity,
hyperreflexia
Minor symptoms: impaired co-ordination, mydriasis, akathisia
These symptoms must not correspond to a psychiatric disorder, or its aggravation, that occurred before the patient took the serotonergic agent.
Infectious, metabolic, endocrine or toxic causes must be excluded.
A neuroleptic treatment must not have been introduced, nor its dose increased, before the symptoms appeared.
38
Slide39Serotonin Syndrome
39
The Hunter Serotonin Toxicity Criteria
Adapted from
Ables AZ, Nagubilli R.. Am Fam Physician. 2010
Serotonin toxicity
In the presence of a serotonergic agent, serotonin toxicity is diagnosed:
Spontaneous clonus is present
Inducible or ocular clonus with agitation or diaphoresis are present
Inducible ocular clonus and increased muscle tone and temperature >38
o
C are present
Tremor and
hyperreflexia
are present
Serotonin toxicity
Serotonin toxicity
Serotonin toxicity
No
No
No
Yes
Yes
Yes
Yes
Slide40Serotonin Syndrome
Risk factors
Administration of 2 or more serotonergic medications
Rarely with monotherapy
PreventionAwareness of risk when prescribing medications that may lead to increased levels of serotonin in the CNSPharmacodynamic interactionsPharmacokinetic interactionsAvoidance of these interactions whenever possible40
Slide41Serotonin Syndrome
Mechanisms that lead to overstimulation of serotonin
Increased precursors of serotonin or its agonists
Buspirone, L-dopa, lithium, LSD, L-tryptophan, trazodone
Decreased serotonin metabolismMAOI – irreversible (phenelzine, tranylcypromine, selegiline)MAOI – reversible (linezolid)Increased serotonin releaseAmphetamines, cocaine, MDMA (“ecstasy”), fenfluramine, reserpineInhibit serotonin reuptakeSSRI, SNRIs, TCAs, meperidine, tramadol
41
Slide42Serotonin Syndrome
The most common drug combinations causing the serotonin syndrome
MAOIs and SSRIs,
MAOIs and TCAs
MAOIs and tryptophanMAOIs and meperidine42
Slide43Serotonin Syndrome
Most common disorders mistaken for Serotonin Syndrome
Infections
Toxic-metabolic delirium
Alcohol withdrawal deliriumExtrapyramidal side-effectsAdrenergic or anticholinergic toxicityNMSSystemic disordersPheochromocytomaCarcinoid tumor43
Slide44Serotonin Syndrome
Clinical course and outcome
Rapid onset
Serotonin syndrome is usually self-limited, with an uneventful resolution, once the offending agent has been discontinued.
44
Slide45Serotonin Syndrome
Treatment
No standardized treatment of serotonin syndrome exists.
Management starts with early recognition of the syndrome, and supportive care.(Mason)
The basic treatment of serotonin syndrome consists ofDiscontinuation of the causative drugsSupportive therapyHydrationCoolingMedications
45
Slide46Serotonin Syndrome
Non-Pharmacologic Treatment
Discontinuation of the causative drugs
Supportive therapy
HydrationCooling46
Slide47Serotonin Syndrome
Pharmacologic Treatment
Several drugs have been used to treat serotonin syndrome.
Cyproheptadine
PropranololChlorpromazine47
Slide48Serotonin Syndrome
Pharmacologic Treatment
Benzodiazepines
Control of agitation
May blunt the hyperadrenergic component of the syndrome48
Slide49Serotonin Syndrome
Pharmacologic Treatment
Cyproheptadine
First-generation antihistamine
Shown in animal studies to prevent the onset of experimentally induced serotonin syndrome.While no randomized control trials have been conducted to evaluate fully the efficacy of cyproheptadine, its use in the treatment of serotonin syndrome has been documented.Mechanism5-HT1A and 5-HT2 receptor antagonists (McDaniel, 2001).Dose (Boyer and Shannon, 2005)May consider an initial dose of 12mg followed by 2mg every 2 hours if symptoms continueMaintenance dosage is 8mg every 6 hours
49
Slide50Serotonin Syndrome
Pharmacologic Treatment
(continued)
Chlorpromazine
Shown to be effective in some cases in the treatment of serotonin syndrome (Graham, 1997; Gillman, 1999)MechanismFairly potent 5-HT2 and 5-HT1A receptor antagonistAdvantagesIt can be administered via an intramuscular injection.
Disadvantages
It can cause hypotension, dystonic reactions, and NMS.
50
Slide51Serotonin Syndrome
Pharmacologic Treatment
(continued)
Propranolol
It has been reported to be effective against serotonin syndrome in humans (Gillman, 1999),Efficiency of propranolol remains unclear.Mechanism5-HT1A receptor antagonist51
Slide52NMS versus 5HT Syndrome
Neuroleptic
Malignant Syndrome
Serotonin Syndrome
Precipitated by
Dopamine antagonists
Serotoninergic agents
Onset
Variable
(1-3 days)
Variable (<1d)
Vital Signs
Hypertension, tachycardia, tachypnea
Hypertension, tachycardia, tachypnea
Temperature
Hyperthermia
Hyperthermia
Mucosa
Sialorrhea
Sialorrhea
Skin
Diaphoresis
Diaphoresis
Mental
Status
Delirium
Delirium
Muscles
“Lead
pipe” rigidity
Increased tone
Reflexes
Hyporeflexia
Hyperreflexia, clonus
Pupils
Normal
Dilated
52
Adapted from
Birmes
et al, CMAJ 2003
Slide53Selected References
Stephan C. Mann, M.D., Stanley N. Caroff, M.D., Paul E. Keck, Jr., M.D., and Arthur Lazarus, M.D., M.B.A. Neuroleptic Malignant Syndrome and Related Conditions, Second Edition, AAPI, 2003
Neuroleptic malignant syndrome. Strawn JR, Keck PE Jr, Caroff SN. Am J Psychiatry. 2007 Jun;164(6):870-6.
Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005 Mar 17;352(11):1112-20.
Birmes P, Coppin D, Schmitt L, Lauque D. Serotonin syndrome: a brief review. CMAJ. 2003 May 27;168(11):1439-42.Ables AZ, Nagubilli R. Prevention, recognition, and management of serotonin syndrome. Am Fam Physician. 2010;81(9
):
1139-42
53